Cardiovascular disease culminates in a syndrome, congestive heart failure (CHF), in which the heart in unable to pump a sufficient quantity of blood to meet the metabolic needs of the individual. The factors that precipitate CHF and drive its progression are the topics of this research program. The proposed research challenges the existing dogmas that the initiation and progression of CHF is caused by weakening of myocyte contractility and that the adult heart is incapable of generating new myocytes. The working hypothesis of this research program is that a progressive reduction in the number of ventricular myocytes, rather than abnormalities in myocyte function, is the primary factor that initiates and causes progression of heart failure. Specific hypotheses are that myocyte death is induced by persistent increases in myocyte Ca2+ and that myocyte death can be offset by new myocyte formation, to slow or reverse CHF progression. To test these ideas we have generated a transgenic mouse with cardiac specific, inducible expression of a subunit (CaV1.2p2a) of the L-type Ca2+ channel, the major Ca2+ influx pathway in cardiac myocytes. Activation of CaV1.2(32a expression leads to increased myocyte Ca2+ influx, Ca2+ transients and contractility which initially culminates in increased ventricular performance. However, after a few months these mice have increased myocyte death, cardiac hypertrophy, ventricular and atrial dilation and reduced cardiac pump function. Interestingly, myocytes still have increased contractility. Preliminary studies also show that activation of the adrenergic signaling pathways, which also increase myocyte contractility, is involved in the initiation and progression of cardiac dysfunction in CaV1.2p2a mice. We have also recently shown that the normal heart has the capacity to generate new myocyte during periods of physiological and pathological growth. The specific aims of the proposed studies are 1) To determine if persistent increases in Ca2+ influx through the L-type Ca2+ channel induces CHF by causing increased myocyte death (via apoptosis and necrosis); 2) To determine if increased myocyte death induces an increase in new myocyte formation which slows the rate of myocyte loss and provides a mechanism for cardiac regeneration if the factors causing myocyte death (CaV1.2p2a expression) are eliminated; and 3) To determine if activation of Pradrenergic receptors in CaV1.2(32a mice exacerbates myocyte death and if activation of p2- adrenergic receptors blunts myocyte death and enhances new myocyte formation. We will also explore the role of myocyte death and new myocyte formation in the other models systems to be studied within this PPG. Support for our hypotheses will identify novel targets for CHF therapy and will change the thinking from current approaches that seek to increase myocyte force generation to those that seek to reduce myocyte death and promote myocyte regeneration.